{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T22:50:28Z","timestamp":1792623028987,"version":"4.5.0"},"reference-count":141,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T00:00:00Z","timestamp":1634688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Currently, herbal and dietary supplements have been widely applied to prevent and treat various diseases. However, the potential toxicities and adverse reactions of herbal and dietary supplements have been increasingly reported, and have gradually attracted widespread attention from clinical pharmacists and physicians. Metabolic activation of specific natural products from herbal and dietary supplements is mediated by hepatic cytochrome P450 or intestinal bacteria, and generates chemical reactive\/toxic metabolites that bind to cellular reduced glutathione or macromolecules, and form reactive metabolites-glutathione\/protein\/DNA adducts, and these protein\/DNA adducts can result in toxicities. The present review focuses on the relation between metabolic activation and toxicities of natural products, and provides updated, comprehensive and critical comment on the toxic mechanisms of reactive metabolites. The key inductive role of metabolic activation in toxicity is highlighted, and frequently toxic functional groups of toxic natural products were summarized. The biotransformation of drug cytochrome P450 or intestinal bacteria involved in metabolic activation were clarified, the reactive metabolites-protein adducts were selected as biomarkers for predicting toxicity. And finally, further perspectives between metabolic activation and toxicities of natural products from herbal and dietary supplements are discussed, to provide a reference for the reasonable and safe usage of herbal and dietary supplements.<\/jats:p>","DOI":"10.3389\/fphar.2021.758468","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T19:29:49Z","timestamp":1634758189000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":37,"title":["Metabolic Activation of the Toxic Natural Products From Herbal and Dietary Supplements Leading to Toxicities"],"prefix":"10.3389","volume":"12","author":[{"given":"Yi-Kun","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen Qun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bi-Kui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.fct.2016.01.018","article-title":"Mode of Action Based Risk Assessment of the Botanical Food-Borne Alkenylbenzene Apiol from Parsley Using Physiologically Based Kinetic (PBK) Modelling and Read-Across from Safrole","volume":"89","author":"Alajlouni","year":"2016","journal-title":"Food Chem. Toxicol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1038\/nrgastro.2017.20","article-title":"Gut Microbiota Modulation of Chemotherapy Efficacy and Toxicity","volume":"14","author":"Alexander","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"R39","DOI":"10.1186\/bcr2090","article-title":"Antiproliferative and Cytostatic Effects of the Natural Product Eupatorin on MDA-MB-468 Human Breast Cancer Cells Due to CYP1-Mediated Metabolism","volume":"10","author":"Androutsopoulos","year":"2008","journal-title":"Breast Cancer Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.canlet.2008.08.032","article-title":"Bioactivation of the Phytoestrogen Diosmetin by CYP1 Cytochromes P450","volume":"274","author":"Androutsopoulos","year":"2009","journal-title":"Cancer Lett."},{"key":"B5","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1080\/00498250802702316","article-title":"Inhibition of Human Glutathione S-Transferases by Curcumin and Analogues","volume":"39","author":"Appiah-Opong","year":"2009","journal-title":"Xenobiotica"},{"key":"B6","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1021\/tx0496993","article-title":"Bioactivation of 4-ipomeanol by CYP4B1: Adduct Characterization and Evidence for an Enedial Intermediate","volume":"18","author":"Baer","year":"2005","journal-title":"Chem. Res. Toxicol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1126\/science.327550","article-title":"Mutagenic Activity of Quercetin and Related Compounds","volume":"197","author":"Bjeldanes","year":"1977","journal-title":"Science"},{"key":"B8","first-page":"5163","article-title":"Strong Evidence from Studies with Brachymorphic Mice and Pentachlorophenol that 1'-sulfo\u00f6xysafrole Is the Major Ultimate Electrophilic and Carcinogenic Metabolite of 1'-hydroxysafrole in Mouse Liver","volume":"43","author":"Boberg","year":"1983","journal-title":"Cancer Res."},{"key":"B9","first-page":"590","article-title":"1'-Hydroxysafrole, a Proximate Carcinogenic Metabolite of Safrole in the Rat and Mouse","volume":"33","author":"Borchert","year":"1973","journal-title":"Cancer Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/0041-008X(82)90361-1","article-title":"Metabolic Activation of 4-ipomeanol by Avian Tissue Microsomes","volume":"65","author":"Buckpitt","year":"1982","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/apt.12109","article-title":"Review Article: Herbal and Dietary Supplement Hepatotoxicity","volume":"37","author":"Bunchorntavakul","year":"2012","journal-title":"Aliment. Pharmacol. Ther."},{"key":"B12","first-page":"243","article-title":"Experimental Progress of Liver Toxicity of Tripterygium Wilfordii and its Mechanism[J]","volume":"7","author":"Chai","year":"2011","journal-title":"Chinese J Experi Traditional Medical Formula"},{"key":"B13","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1021\/acs.chemrestox.5b00427","article-title":"9-Glutathionyl-6,7-dihydro-1-hydroxymethyl-5H-pyrrolizine Is the Major Pyrrolic Glutathione Conjugate of Retronecine-type Pyrrolizidine Alkaloids in Liver Microsomes and in Rats","volume":"29","author":"Chen","year":"2016","journal-title":"Chem. Res. Toxicol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1021\/tx060143k","article-title":"Characterization of the Amino Acid Adducts of the Enedial Derivative of Teucrin A","volume":"19","author":"Druckova","year":"2006","journal-title":"Chem. Res. Toxicol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1021\/tx7001405","article-title":"Identification of the Protein Targets of the Reactive Metabolite of Teucrin A In Vivo in the Rat","volume":"20","author":"Druckova","year":"2007","journal-title":"Chem. Res. Toxicol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"3167","DOI":"10.1002\/rcm.5211","article-title":"Metabolite Identification of Triptolide by Data-dependent Accurate Mass Spectrometric Analysis in Combination with Online Hydrogen\/deuterium Exchange and Multiple Data-Mining Techniques","volume":"25","author":"Du","year":"2011","journal-title":"Rapid Commun. Mass. Spectrom."},{"key":"B17","doi-asserted-by":"publisher","first-page":"177","DOI":"10.3389\/fphar.2013.00177","article-title":"The Growing Use of Herbal Medicines: Issues Relating to Adverse Reactions and Challenges in Monitoring Safety","volume":"4","author":"Ekor","year":"2013","journal-title":"Front. Pharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"417","DOI":"10.19540\/j.cnki.cjcmm.2018.0009","article-title":"Current Research Situation of Nephrotoxicity of Chinese Herbal Medicine","volume":"43","author":"Feng","year":"2018","journal-title":"Zhongguo Zhong Yao Za Zhi"},{"key":"B19","doi-asserted-by":"publisher","first-page":"S197","DOI":"10.1016\/j.toxlet.2017.07.859","article-title":"In Vitro screening of Acute Hepatic Cytotoxicity of Pyrrolizidine Alkaloids in Human and Rodent Hepatic Cell Lines","volume":"280","author":"Forsch","year":"2017","journal-title":"Toxicol. Lett."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1081\/dmr-120028426","article-title":"Pyrrolizidine Alkaloids-Ggenotoxicity, Metabolism Enzymes, Metabolic Activation, and Mechanisms","volume":"36","author":"Fu","year":"2004","journal-title":"Drug Metab. Rev."},{"key":"B21","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1021\/acs.chemrestox.6b00297","article-title":"Pyrrolizidine Alkaloids: Metabolic Activation Pathways Leading to Liver Tumor Initiation","volume":"30","author":"Fu","year":"2017","journal-title":"Chem. Res. Toxicol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.2169\/internalmedicine.49.3509","article-title":"Toxic Hepatitis Induced by show-Wu-pian, a Chinese Herbal Preparation","volume":"49","author":"Furukawa","year":"2010","journal-title":"Intern. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1021\/tx0496791","article-title":"Dansyl Glutathione as a Trapping Agent for the Quantitative Estimation and Identification of Reactive Metabolites","volume":"18","author":"Gan","year":"2005","journal-title":"Chem. Res. Toxicol."},{"key":"B24","first-page":"96","article-title":"Review of Studies of Bisbenzylisoquinoline Alkaloid (BBI) on Distribution in Higher Plant and Physiological Activities[J]","volume-title":"Nat. Prod. Res. Dev.","author":"Gao","year":"1998"},{"key":"B25","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1111\/j.1742-7843.2011.00781.x","article-title":"Two Contemporary Cases of Hepatitis Associated with Teucrium Chamaedrys L. Decoction Use: Case Reports and Review of Literature","volume":"109","author":"Gori","year":"2011","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1007\/s12161-014-9855-1","article-title":"Liquid Chromatography Tandem Mass Spectrometry Detection of Targeted Pyrrolizidine Alkaloids in Honeys Purchased within Ireland","volume":"8","author":"Griffin","year":"2015","journal-title":"Food Anal. Methods"},{"key":"B27","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/978-3-319-43806-1_8","article-title":"Metabolomics Applications in Herbal Medicine","volume-title":"Toxicology of Herbal Products","author":"Hanhineva","year":"2017"},{"key":"B28","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1142\/S0192415x12500668","article-title":"Traditional Japanese Herbal (Kampo) Medicines and Treatment of Ocular Diseases: A Review","volume":"40","author":"Hayasaka","year":"2012","journal-title":"Am. J. Chin. Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1002\/hep.31723","article-title":"Mutational Signature Analysis Reveals Widespread Contribution of Pyrrolizidine Alkaloid Exposure to Human Liver Cancer","volume":"74","author":"He","year":"2021","journal-title":"Hepatology"},{"key":"B30","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1007\/s00204-020-02921-0","article-title":"Lung Injury Induced by Pyrrolizidine Alkaloids Depends on Metabolism by Hepatic Cytochrome P450s and Blood Transport of Reactive Metabolites","volume":"95","author":"He","year":"2021","journal-title":"Arch. Toxicol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.toxlet.2020.05.004","article-title":"Cortex Dictamni-Induced Liver Injury in Mice: The Role of P450-Mediated Metabolic Activation of Furanoids","volume":"330","author":"Huang","year":"2020","journal-title":"Toxicol. Lett."},{"key":"B32","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/0041-008X(87)90306-1","article-title":"Decreased Pneumotoxicity of Deuterated 3-methylindole: Bioactivation Requires Methyl C-H Bond Breakage","volume":"90","author":"Huijzer","year":"1987","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"4089019","DOI":"10.1155\/2017\/4089019","article-title":"Characteristics of Herbal Medicine Users and Adverse Events Experienced in South Korea: A Survey Study","volume":"2017","author":"Jang","year":"2017","journal-title":"Evid. Based Complement. Alternat Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1021\/tx040001v","article-title":"Human Cytochrome P450 Enzyme Specificity for Bioactivation of Safrole to the Proximate Carcinogen 1'-hydroxysafrole","volume":"17","author":"Jeurissen","year":"2004","journal-title":"Chem. Res. Toxicol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1021\/tx050267h","article-title":"Human Cytochrome P450 Enzymes of Importance for the Bioactivation of Methyleugenol to the Proximate Carcinogen 1'-hydroxymethyleugenol","volume":"19","author":"Jeurissen","year":"2006","journal-title":"Chem. Res. Toxicol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1021\/tx700012d","article-title":"Human Cytochrome P450 Enzyme Specificity for the Bioactivation of Estragole and Related Alkenylbenzenes","volume":"20","author":"Jeurissen","year":"2007","journal-title":"Chem. Res. Toxicol."},{"key":"B37","first-page":"257","article-title":"Adverse Drug Reaction of Compound Prescription of Huangyaozi(Dioscorea Bulbifera L.) in Clinical Trial and its Management","author":"Jiang","year":"2004","journal-title":"Chin. J Evid-Based Med."},{"key":"B38","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.tiv.2016.11.006","article-title":"Metabolic-induced Cytotoxicity of Diosbulbin B in CYP3A4-Expressing Cells","volume":"38","author":"Jiang","year":"2017","journal-title":"Toxicol. Vitro"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1021\/acs.chemrestox.8b00117","article-title":"CYP3A Activation and Glutathione Depletion Aggravate Emodin-Induced Liver Injury","volume":"31","author":"Jiang","year":"2018","journal-title":"Chem. Res. Toxicol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1124\/jpet.109.162297","article-title":"Pulmonary Toxicity and Metabolic Activation of Dauricine in CD-1 Mice","volume":"332","author":"Jin","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B41","doi-asserted-by":"publisher","first-page":"2142","DOI":"10.1021\/tx200290s","article-title":"Pulmonary Toxicity and Metabolic Activation of Tetrandrine in CD-1 Mice","volume":"24","author":"Jin","year":"2011","journal-title":"Chem. Res. Toxicol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.taap.2012.03.025","article-title":"CYP3A-mediated Apoptosis of Dauricine in Cultured Human Bronchial Epithelial Cells and in Lungs of CD-1 Mice","volume":"261","author":"Jin","year":"2012","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"e177","DOI":"10.1016\/j.ddtec.2012.09.011","article-title":"Inhibition of Cytochrome P450 Enzymes and Biochemical Aspects of Mechanism-Based Inactivation (MBI)","volume":"10","author":"Kamel","year":"2013","journal-title":"Drug Discov. Today Technol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1007\/s12272-011-0420-9","article-title":"Role of Metabolism by Intestinal Bacteria in Arbutin-Induced Toxicity In Vitro","volume":"34","author":"Kang","year":"2011","journal-title":"Arch. Pharm. Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1007\/s12272-012-0418-y","article-title":"Role of Metabolism by Human Intestinal Microflora in Geniposide-Induced Toxicity in HepG2 Cells","volume":"35","author":"Kang","year":"2012","journal-title":"Arch. Pharm. Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1751","DOI":"10.1002\/art.1780361217","article-title":"Resolution of Severe Lupus Nephritis Associated with Tripterygium Wilfordii Hook F Ingestion","volume":"36","author":"Kao","year":"2010","journal-title":"Arthritis Rheum."},{"key":"B47","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1248\/bpb.21.628","article-title":"Metabolism of Puerarin and Daidzin by Human Intestinal Bacteria and Their Relation to In Vitro Cytotoxicity","volume":"21","author":"Kim","year":"1998","journal-title":"Biol. Pharm. Bull."},{"key":"B48","doi-asserted-by":"publisher","first-page":"13184","DOI":"10.1021\/bi981198r","article-title":"Mechanism-Based Inactivation of Cytochrome P450 2B1 by 8-Methoxypsoralen and Several Other Furanocoumarins","volume":"37","author":"Koenigs","year":"1998","journal-title":"Biochemistry"},{"key":"B49","doi-asserted-by":"publisher","first-page":"493","DOI":"10.5009\/gnl.2011.5.4.493","article-title":"Drug-Induced Liver Injury: Twenty Five Cases of Acute Hepatitis Following Ingestion of Polygonum Multiflorum Thunb","volume":"5","author":"Kyoung Ah","year":"2011","journal-title":"Gut Liver"},{"key":"B50","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1002\/rcm.7518","article-title":"Tandem Mass Spectrometric Analysis of S- and N-Linked Glutathione Conjugates of Pulegone and Menthofuran and Identification of P450 Enzymes Mediating Their Formation","volume":"30","author":"Lassila","year":"2016","journal-title":"Rapid Commun. Mass. Spectrom."},{"key":"B51","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1002\/hep.510240134","article-title":"Hepatotoxicity of the Herbal Medicine Germander: Metabolic Activation of its Furano Diterpenoids by Cytochrome P450 3A Depletes Cytoskeleton-Associated Protein Thiols and Forms Plasma Membrane Blebs in Rat Hepatocytes","volume":"24","author":"Lekehal","year":"1996","journal-title":"Hepatology"},{"key":"B52","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1021\/tx200033v","article-title":"Profiling the Reactive Metabolites of Xenobiotics Using Metabolomic Technologies","volume":"24","author":"Li","year":"2011","journal-title":"Chem. Res. Toxicol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.apsb.2012.02.010","article-title":"LC-MS-Based Metabolomics in Profiling of Drug Metabolism and Bioactivation","volume":"2","author":"Li","year":"2012","journal-title":"Acta Pharm. Sin. B"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1021\/acs.chemrestox.9b00081","article-title":"Metabolic Activation and Cytotoxicity of Aloe-Emodin Mediated by Sulfotransferases","volume":"32","author":"Li","year":"2019","journal-title":"Chem. Res. Toxicol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"114624","DOI":"10.1016\/j.taap.2019.114624","article-title":"Role of Intestinal Microbiota-Mediated Genipin Dialdehyde Intermediate Formation in Geniposide-Induced Hepatotoxicity in Rats","volume":"377","author":"Li","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.1124\/dmd.114.059261","article-title":"Cytochrome P450-Mediated Metabolic Activation of Diosbulbin B","volume":"42","author":"Lin","year":"2014","journal-title":"Drug Metab. Dispos"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1737","DOI":"10.1021\/acs.chemrestox.5b00174","article-title":"In Vitro and In Vivo Studies of the Metabolic Activation of 8-Epidiosbulbin E Acetate","volume":"28","author":"Lin","year":"2015","journal-title":"Chem. Res. Toxicol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.toxlet.2016.10.007","article-title":"Lysine- and Cysteine-Based Protein Adductions Derived from Toxic Metabolites of 8-Epidiosbulbin E Acetate","volume":"264","author":"Lin","year":"2016","journal-title":"Toxicol. Lett."},{"key":"B59","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1021\/acs.chemrestox.5b00501","article-title":"Role of Metabolic Activation in 8-Epidiosbulbin E Acetate-Induced Liver Injury: Mechanism of Action of the Hepatotoxic Furanoid","volume":"29","author":"Lin","year":"2016","journal-title":"Chem. Res. Toxicol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1021\/acs.chemrestox.8b00071","article-title":"In Vitro DNA Adduction Resulting from Metabolic Activation of Diosbulbin B and 8-Epidiosbulbin E Acetate","volume":"32","author":"Lin","year":"2019","journal-title":"Chem. Res. Toxicol."},{"key":"B61","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.jchromb.2013.08.015","article-title":"Metabolite Profiling and Identification of Triptolide in Rats","volume":"939","author":"Liu","year":"2013","journal-title":"J. Chromatogr. B Analyt Technol. Biomed. Life Sci."},{"key":"B62","doi-asserted-by":"publisher","first-page":"7150391","DOI":"10.1155\/2016\/7150391","article-title":"Research Advances on Hepatotoxicity of Herbal Medicines in China","volume":"2016","author":"Liu","year":"2016","journal-title":"Biomed. Res. Int."},{"key":"B63","doi-asserted-by":"publisher","first-page":"3054","DOI":"10.1021\/acs.chemrestox.0c00475","article-title":"Cytochrome P450 Mediated Bioactivation of Rutaevin, a Bioactive and Potentially Hepatotoxic Component of Evodia Rutaecarpa","volume":"33","author":"Liu","year":"2020","journal-title":"Chem. Res. Toxicol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1021\/acs.chemrestox.8b00369","article-title":"Pyrrole-Hemoglobin Adducts, a More Feasible Potential Biomarker of Pyrrolizidine Alkaloid Exposure","volume":"32","author":"Ma","year":"2019","journal-title":"Chem. Res. Toxicol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.toxlet.2016.05.002","article-title":"Interim Relative Potency Factors for the Toxicological Risk Assessment of Pyrrolizidine Alkaloids in Food and Herbal Medicines","volume":"263","author":"Merz","year":"2016","journal-title":"Toxicol. Lett."},{"key":"B67","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1021\/acs.chemrestox.0c00483","article-title":"Mechanism-Based Inactivation of Cytochrome P450 Enzymes: Computational Insights","volume":"34","author":"Mirzaei","year":"2021","journal-title":"Chem. Res. Toxicol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/0165-1110(83)90018-0","article-title":"Cycasin and its Mutagenic Metabolites","volume":"114","author":"Morgan","year":"1983","journal-title":"Mutat. Res."},{"key":"B69","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1002\/hep.28813","article-title":"Liver Injury from Herbal and Dietary Supplements","volume":"65","author":"Navarro","year":"2016","journal-title":"Hepatology"},{"key":"B70","doi-asserted-by":"publisher","first-page":"181","DOI":"10.4103\/0253-7613.129313","article-title":"Hepatotoxicity of Teucrium Chamaedrys L. Decoction: Role of Difference in the Harvesting Area and Preparation Method","volume":"46","author":"Nencini","year":"2014","journal-title":"Indian J. Pharmacol."},{"key":"B71","doi-asserted-by":"publisher","first-page":"825","DOI":"10.18433\/j3bg7j","article-title":"Hepatotoxicity of Pyrrolizidine Alkaloids","volume":"18","author":"Neuman","year":"2015","journal-title":"J. Pharm. Pharm. Sci."},{"key":"B72","volume-title":"Metabolism of (-)-Ngaione, a Toxic Furanoid Ketone from Myoporum Species","author":"Ng","year":"1983"},{"key":"B73","doi-asserted-by":"publisher","first-page":"461160","DOI":"10.1016\/j.chroma.2020.461160","article-title":"Application of a Fluorous Derivatization Method for Characterization of Glutathione-Trapped Reactive Metabolites with Liquid Chromatography-Tandem Mass Spectrometry Analysis","volume":"1622","author":"Nishijo","year":"2020","journal-title":"J. Chromatogr. A."},{"key":"B74","doi-asserted-by":"publisher","first-page":"4896","DOI":"10.1021\/jm300065h","article-title":"Mechanism-based Inactivation (MBI) of Cytochrome P450 Enzymes: Structure-Activity Relationships and Discovery Strategies to Mitigate Drug-Drug Interaction Risks","volume":"55","author":"Orr","year":"2012","journal-title":"J. Med. Chem."},{"key":"B75","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1111\/j.1365-2885.2011.01339.x","article-title":"Bioactivation of 4-Ipomeanol by a CYP4B Enzyme in Bovine Lung and Inhibition by HET0016","volume":"35","author":"Parkinson","year":"2012","journal-title":"J. Vet. Pharmacol. Ther."},{"key":"B76","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1093\/toxsci\/kft123","article-title":"Generation and Characterization of a Cyp4b1 Null Mouse and the Role of CYP4B1 in the Activation and Toxicity of Ipomeanol","volume":"134","author":"Parkinson","year":"2013","journal-title":"Toxicol. Sci."},{"key":"B77","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1124\/dmd.116.070003","article-title":"Species Differences in Microsomal Oxidation and Glucuronidation of 4-Ipomeanol: Relationship to Target Organ Toxicity","volume":"44","author":"Parkinson","year":"2016","journal-title":"Drug Metab. Dispos"},{"key":"B78","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1016\/j.jpba.2012.06.026","article-title":"Identification of In Vivo and In Vitro Metabolites of Triptolide by Liquid Chromatography-Tandem Mass Spectrometry","volume":"70","author":"Peng","year":"2012","journal-title":"J. Pharm. Biomed. Anal."},{"key":"B79","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1021\/tx3003824","article-title":"Reactive Metabolites in the Biotransformation of Molecules Containing a Furan Ring","volume":"26","author":"Peterson","year":"2013","journal-title":"Chem. Res. Toxicol."},{"key":"B80","doi-asserted-by":"publisher","first-page":"195","DOI":"10.4314\/ajtcam.v7i3.54775","article-title":"Ethnoveterinary Uses of Medicinal Plants Among Traditional Herbal Healers in Alaknanda Catchment of Uttarakhand, India","volume":"7","author":"Phondani","year":"2010","journal-title":"Afr. J. Tradit Complement. Altern. Med."},{"key":"B81","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/j.biopha.2016.08.009","article-title":"Structure Related Effects of Flavonoid Aglycones on Cell Cycle Progression of HepG2 Cells: Metabolic Activation of Fisetin and Quercetin by Catechol-O-Methyltransferase (COMT)","volume":"83","author":"Po\u00f3r","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"B82","doi-asserted-by":"publisher","first-page":"7","DOI":"10.7861\/clinmedicine.13-1-7","article-title":"Adverse Effects of Herbal Medicines: an Overview of Systematic Reviews","volume":"13","author":"Posadzki","year":"2013","journal-title":"Clin. Med. (Lond)"},{"key":"B83","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1021\/acs.chemrestox.6b00191","article-title":"Chemical Reactivity of Emodin and its Oxidative Metabolites to Thiols","volume":"29","author":"Qin","year":"2016","journal-title":"Chem. Res. Toxicol."},{"key":"B84","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1021\/acs.chemrestox.8b00026","article-title":"In Vitro and In Vivo Studies of the Electrophilicity of Physcion and its Oxidative Metabolites","volume":"31","author":"Qin","year":"2018","journal-title":"Chem. Res. Toxicol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1126\/science.6719117","article-title":"Reactive Metabolites from the Bioactivation of Toxic Methylfurans","volume":"224","author":"Ravindranath","year":"1984","journal-title":"Science"},{"key":"B86","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/0041-008X(86)90389-3","article-title":"2-Methylfuran Toxicity in Rats-Rrole of Metabolic Activation In Vivo","volume":"85","author":"Ravindranath","year":"1986","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B87","doi-asserted-by":"publisher","first-page":"500","DOI":"10.2174\/0929867321666140916123022","article-title":"Biotransformation of Endocrine Disrupting Compounds by Selected Phase I and Phase II Enzymes-Fformation of Estrogenic and Chemically Reactive Metabolites by Cytochromes P450 and Sulfotransferases","volume":"22","author":"Reinen","year":"2015","journal-title":"Curr. Med. Chem."},{"key":"B88","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1021\/tx500109s","article-title":"Impact of Structural and Metabolic Variations on the Toxicity and Carcinogenicity of Hydroxy- and Alkoxy-Substituted Allyl- and Propenylbenzenes","volume":"27","author":"Rietjens","year":"2014","journal-title":"Chem. Res. Toxicol."},{"key":"B89","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1039\/c5np00076a","article-title":"Pyrrolizidine Alkaloids: Occurrence, Biology, and Chemical Synthesis","volume":"34","author":"Robertson","year":"2017","journal-title":"Nat. Prod. Rep."},{"key":"B90","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1021\/tx500071q","article-title":"Metabolic Activation of Pyrrolizidine Alkaloids: Insights into the Structural and Enzymatic Basis","volume":"27","author":"Ruan","year":"2014","journal-title":"Chem. Res. Toxicol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1021\/tx4004159","article-title":"Lack of Metabolic Activation and Predominant Formation of an Excreted Metabolite of Nontoxic Platynecine-type Pyrrolizidine Alkaloids","volume":"27","author":"Ruan","year":"2014","journal-title":"Chem. Res. Toxicol."},{"key":"B92","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.cbi.2014.10.014","article-title":"Demethylation of Neferine in Human Liver Microsomes and Formation of Quinone Methide Metabolites Mediated by CYP3A4 Accentuates its Cytotoxicity","volume":"224","author":"Shen","year":"2014","journal-title":"Chem. Biol. Interact"},{"key":"B93","doi-asserted-by":"publisher","first-page":"1372","DOI":"10.1002\/jat.3106","article-title":"Cytotoxicity of Luteolin in Primary Rat Hepatocytes: the Role of CYP3A-Mediated Ortho-Benzoquinone Metabolite Formation and Glutathione Depletion","volume":"35","author":"Shi","year":"2015","journal-title":"J. Appl. Toxicol."},{"key":"B94","doi-asserted-by":"publisher","first-page":"100386","DOI":"10.1016\/j.dmpk.2021.100386","article-title":"Development of Fluorescent-Labeled Trapping Reagents Based on Cysteine to Detect Soft and Hard Electrophilic Reactive Metabolites","volume":"39","author":"Shibazaki","year":"2021","journal-title":"Drug Metab. Pharmacokinet."},{"key":"B95","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1021\/tx9702087","article-title":"Evidence Supporting the Formation of 2,3-Epoxy-3-Methylindoline: a Reactive Intermediate of the Pneumotoxin 3-methylindole","volume":"11","author":"Skordos","year":"1998","journal-title":"Chem. Res. Toxicol."},{"key":"B96","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1016\/j.fct.2005.11.006","article-title":"In Vitro basal and Metabolism-Mediated Cytotoxicity of Flavonoids","volume":"44","author":"Soares","year":"2006","journal-title":"Food Chem. Toxicol."},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.21876","article-title":"In Vitro and In Vivo Metabolic Activation of Berbamine to Quinone Methide Intermediate","volume":"31","author":"Sun","year":"2017","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"B98","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.cbi.2018.04.015","article-title":"Cytochrome P450 Mediated Metabolic Activation of Chrysophanol","volume":"289","author":"Sun","year":"2018","journal-title":"Chem. Biol. Interact"},{"key":"B99","doi-asserted-by":"publisher","first-page":"3320","DOI":"10.1016\/j.fct.2012.06.030","article-title":"Bioactivation of the Citrus Flavonoid Nobiletin by CYP1 Enzymes in MCF7 Breast Adenocarcinoma Cells","volume":"50","author":"Surichan","year":"2012","journal-title":"Food Chem. Toxicol."},{"key":"B100","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.tiv.2018.04.001","article-title":"Tangeretin Inhibits the Proliferation of Human Breast Cancer Cells via CYP1A1\/CYP1B1 Enzyme Induction and CYP1A1\/CYP1B1-Mediated Metabolism to the Product 4' Hydroxy Tangeretin","volume":"50","author":"Surichan","year":"2018","journal-title":"Toxicol. Vitro"},{"key":"B101","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.fct.2018.01.047","article-title":"Nobiletin Bioactivation in MDA-MB-468 Breast Cancer Cells by Cytochrome P450 CYP1 Enzymes","volume":"113","author":"Surichan","year":"2018","journal-title":"Food Chem. Toxicol."},{"key":"B102","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1631\/jzus.B1000135","article-title":"Pyrrolizidine Alkaloids-Containing Chinese Medicines in the Chinese Pharmacopoeia and Related Safety Concerns","volume":"46","author":"Tang","year":"2011","journal-title":"Yao Xue Xue Bao"},{"key":"B103","doi-asserted-by":"publisher","first-page":"1735","DOI":"10.1002\/art.10411","article-title":"Benefit of an Extract of Tripterygium Wilfordii Hook F in Patients with Rheumatoid Arthritis: a Double-Blind, Placebo-Controlled Study","volume":"46","author":"Tao","year":"2002","journal-title":"Arthritis Rheum."},{"key":"B104","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/s1665-2681(19)30796-3","article-title":"Traditional Chinese Medicine and Herbal Hepatotoxicity: a Tabular Compilation of Reported Cases","volume":"14","author":"Teschke","year":"2015","journal-title":"Ann. Hepatol."},{"key":"B105","first-page":"567","article-title":"Menthofuran-Dependent and Independent Aspects of Pulegone Hepatotoxicity: Roles of Glutathione","volume":"253","author":"Thomassen","year":"1990","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B106","doi-asserted-by":"publisher","first-page":"1737","DOI":"10.1007\/s00204-015-1584-8","article-title":"CYP3A5 Mediates Bioactivation and Cytotoxicity of Tetrandrine","volume":"90","author":"Tian","year":"2016","journal-title":"Arch. Toxicol."},{"key":"B107","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1021\/tx800426x","article-title":"A Targeted Proteomics Approach to the Identification of Peptides Modified by Reactive Metabolites","volume":"22","author":"Tzouros","year":"2009","journal-title":"Chem. Res. Toxicol."},{"key":"B108","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1006\/taap.1993.1237","article-title":"CYP4B1 Activates 4-ipomeanol in Rat Lung","volume":"123","author":"Verschoyle","year":"1993","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B109","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/0027-5107(90)90130-V","article-title":"Metabolic Activation of Quercetin Mutagenicity","volume":"232","author":"Vrijsen","year":"1990","journal-title":"Mutat. Res."},{"key":"B110","article-title":"P450-Mediated Metabolic Activation of Dauricine: Identification of Glutathione Conjugates in Human Liver Microsomes and in Rats[C]","author":"Wang","year":"2008"},{"key":"B111","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/s00210-009-0470-4","article-title":"Protective Effect of Selaginellin on Glutamate-Induced Cytotoxicity and Apoptosis in Differentiated PC12 Cells","volume":"381","author":"Wang","year":"2010","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"B112","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1080\/10590501.2014.969980","article-title":"Metabolic Activation of Pyrrolizidine Alkaloids Leading to Phototoxicity and Photogenotoxicity in Human HaCaT Keratinocytes","volume":"32","author":"Wang","year":"2014","journal-title":"J. Environ. Sci. Health C Environ. Carcinog. Ecotoxicol. Rev."},{"key":"B113","doi-asserted-by":"publisher","first-page":"10755","DOI":"10.1021\/ac502796x","article-title":"Selective and Sensitive Platform for Function-Based Screening of Potentially Harmful Furans","volume":"86","author":"Wang","year":"2014","journal-title":"Anal. Chem."},{"key":"B114","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.aca.2015.09.017","article-title":"Detection of Cysteine- and Lysine-Based Protein Adductions by Reactive Metabolites of 2,5-dimethylfuran","volume":"896","author":"Wang","year":"2015","journal-title":"Anal. Chim. Acta"},{"key":"B115","doi-asserted-by":"publisher","first-page":"249","DOI":"10.3390\/toxins9080249","article-title":"Chemical Identity of Interaction of Protein with Reactive Metabolite of Diosbulbin B In Vitro and In Vivo","volume":"9","author":"Wang","year":"2017","journal-title":"Toxins (Basel)"},{"key":"B116","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1002\/ptr.5987","article-title":"Efficacy and Safety of Tripterygium Wilfordii Hook F for CKD in Mainland China: A Systematic Review and Meta-Analysis","volume":"32","author":"Wang","year":"2017","journal-title":"Phytother Res."},{"key":"B117","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.1124\/dmd.117.077818","article-title":"Metabolic Epoxidation Is a Critical Step for the Development of Benzbromarone-Induced Hepatotoxicity","volume":"45","author":"Wang","year":"2017","journal-title":"Drug Metab. Dispos"},{"key":"B118","doi-asserted-by":"publisher","first-page":"513842","DOI":"10.1093\/ecam\/neq067","article-title":"Traditional Japanese Kampo Medicine: Clinical Research between Modernity and Traditional Medicine-The State of Research and Methodological Suggestions for the Future","volume":"2011","author":"Watanabe","year":"2011","journal-title":"Evid. Based Complement. Alternat Med."},{"key":"B119","doi-asserted-by":"publisher","first-page":"2040","DOI":"10.1021\/acschembio.7b00346","article-title":"Quantitative Chemical Proteomic Profiling of the In Vivo Targets of Reactive Drug Metabolites","volume":"12","author":"Whitby","year":"2017","journal-title":"ACS Chem. Biol."},{"key":"B120","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.fct.2017.10.051","article-title":"Cytochrome P450 CYP1 Metabolism of Hydroxylated Flavones and Flavonols: Selective Bioactivation of Luteolin in Breast Cancer Cells","volume":"110","author":"Wilsher","year":"2017","journal-title":"Food Chem. Toxicol."},{"key":"B121","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.trsl.2016.08.002","article-title":"Gut Microbiome Interactions with Drug Metabolism, Efficacy, and Toxicity","volume":"179","author":"Wilson","year":"2017","journal-title":"Transl Res."},{"key":"B122","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1007\/978-1-4471-6539-2_15","article-title":"The Modulation of Drug Efficacy and Toxicity by the Gut Microbiome","volume-title":"Metabonomics and Gut Microbiota in Nutrition and Disease","author":"Wilson","year":"2015"},{"key":"B123","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1021\/tx500417q","article-title":"7-glutathione Pyrrole Adduct: a Potential DNA Reactive Metabolite of Pyrrolizidine Alkaloids","volume":"28","author":"Xia","year":"2015","journal-title":"Chem. Res. Toxicol."},{"key":"B124","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1021\/acs.chemrestox.6b00120","article-title":"Pyrrolizidine Alkaloid-Protein Adducts: Potential Non-invasive Biomarkers of Pyrrolizidine Alkaloid-Induced Liver Toxicity and Exposure","volume":"29","author":"Xia","year":"2016","journal-title":"Chem. Res. Toxicol."},{"key":"B125","doi-asserted-by":"publisher","first-page":"4111","DOI":"10.1007\/s00216-016-9505-0","article-title":"Detection of Protein Adduction Derived from Dauricine by Alkaline Permethylation","volume":"408","author":"Xie","year":"2016","journal-title":"Anal. Bioanal. Chem."},{"key":"B126","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cbi.2018.01.001","article-title":"In Vitro and In Vivo Metabolic Activation of Rhein and Characterization of Glutathione Conjugates Derived from Rhein","volume":"283","author":"Xu","year":"2018","journal-title":"Chem. Biol. Interact"},{"key":"B127","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.toxlet.2011.05.003","article-title":"Knockout of Hepatic P450 Reductase Aggravates Triptolide-Induced Toxicity","volume":"205","author":"Xue","year":"2011","journal-title":"Toxicol. Lett."},{"key":"B128","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1177\/0748233708093727","article-title":"Metabolic Activation of Retronecine and Retronecine N-Oxide - Formation of DHP-Derived DNA Adducts","volume":"24","author":"Yan","year":"2008","journal-title":"Toxicol. Ind. Health"},{"key":"B129","doi-asserted-by":"publisher","first-page":"1737","DOI":"10.1124\/dmd.114.058222","article-title":"Metabolism of Diosbulbin B In Vitro and In Vivo in Rats: Formation of Reactive Metabolites and Human Enzymes Involved","volume":"42","author":"Yang","year":"2014","journal-title":"Drug Metab. Dispos"},{"key":"B130","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1124\/dmd.112.048678","article-title":"Characterization of Differential Cocaine Metabolism in Mouse and Rat through Metabolomics-Guided Metabolite Profiling","volume":"41","author":"Yao","year":"2013","journal-title":"Drug Metab. Dispos"},{"key":"B131","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1016\/j.toxlet.2009.10.028","article-title":"Effects of Cytochrome P4503A Inducer Dexamethasone on the Metabolism and Toxicity of Triptolide in Rat","volume":"192","author":"Ye","year":"2010","journal-title":"Toxicol. Lett."},{"key":"B132","doi-asserted-by":"publisher","first-page":"2023","DOI":"10.1021\/acs.chemrestox.7b00227","article-title":"Mechanism of Error-free DNA Replication Past Lucidin-Derived DNA Damage by Human DNA Polymerase \u03ba","volume":"30","author":"Yockey","year":"2017","journal-title":"Chem. Res. Toxicol."},{"key":"B133","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1055\/s-2006-959772","article-title":"Diosbulbin-B from the Leaves and Stems of Dioscorea Bulbifera: 1H-1H and 13C-1H COSY NMR Studies","volume":"59","author":"Yonemitsu","year":"1993","journal-title":"Planta Med."},{"key":"B134","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1021\/tx00011a001","article-title":"Mechanisms of 3-methylindole Pneumotoxicity","volume":"2","author":"Yost","year":"1989","journal-title":"Chem. Res. Toxicol."},{"key":"B135","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1021\/tx5002145","article-title":"Identification of Amino Acid and Glutathione N-Conjugates of Toosendanin: Bioactivation of the Furan Ring Mediated by CYP3A4","volume":"27","author":"Yu","year":"2014","journal-title":"Chem. Res. Toxicol."},{"key":"B136","doi-asserted-by":"publisher","first-page":"5742","DOI":"10.1021\/acs.jafc.6b01872","article-title":"Metabolic Activation of Rhein: Insights into the Potential Toxicity Induced by Rhein-Containing Herbs","volume":"64","author":"Yuan","year":"2016","journal-title":"J. Agric. Food Chem."},{"key":"B137","doi-asserted-by":"publisher","first-page":"2208","DOI":"10.1021\/acs.chemrestox.0c00228","article-title":"Cytochrome P450 3A4-Mediated Bioactivation and its Role in Nomilin-Induced Hepatotoxicity","volume":"33","author":"Zhang","year":"2020","journal-title":"Chem. Res. Toxicol."},{"key":"B138","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/03602532.2020.1828910","article-title":"Mechanism-based Inactivation of Cytochrome P450 Enzymes by Natural Products Based on Metabolic Activation","volume":"52","author":"Zhang","year":"2020","journal-title":"Drug Metab. Rev."},{"key":"B139","doi-asserted-by":"publisher","first-page":"172ra22","DOI":"10.1126\/scitranslmed.3005114","article-title":"Melamine-Induced Renal Toxicity Is Mediated by the Gut Microbiota","volume":"5","author":"Zheng","year":"2013","journal-title":"Sci. Transl Med."},{"key":"B140","doi-asserted-by":"publisher","first-page":"4328","DOI":"10.1021\/acs.jafc.9b00893","article-title":"Metabolic Activation of Myristicin and its Role in Cellular Toxicity","volume":"67","author":"Zhu","year":"2019","journal-title":"J. Agric. Food Chem."},{"key":"B141","doi-asserted-by":"publisher","first-page":"2158","DOI":"10.1124\/dmd.113.054056","article-title":"Assessment of the Roles of P-Glycoprotein and Cytochrome P450 in Triptolide-Induced Liver Toxicity in sandwich-cultured Rat Hepatocyte Model","volume":"41","author":"Zhuang","year":"2013","journal-title":"Drug Metab. Dispos"},{"key":"B142","doi-asserted-by":"publisher","first-page":"eaat9931","DOI":"10.1126\/science.aat9931","article-title":"Separating Host and Microbiome Contributions to Drug Pharmacokinetics and Toxicity","volume":"363","author":"Zimmermann","year":"2019","journal-title":"Science"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.758468\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T19:29:59Z","timestamp":1634758199000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.758468\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,20]]},"references-count":141,"alternative-id":["10.3389\/fphar.2021.758468"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.758468","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,20]]},"article-number":"758468"}}